Lung cancer is the most common form of cancer mortality in men and women in the United States, and represents a significant burden on health care resources. Our long-term objective is to characterize lung cancer susceptibility gene(s), as it will allow identification of individuals at especially high risk (including former smokers) who can then be targeted for intensive efforts at smoking prevention, environmental risk reduction, and possibly chemoprevention. Accumulated evidence suggests that there are genetic susceptibility components in lung cancer, and that gene-environment interactions are important. Familial aggregation of lung cancer has been observed and segregation analysis studies have suggested that differential susceptibility to lung cancer may be explained by Mendelian codominant inheritance of a major autosomal gene(s) that acts in conjunction with cigarette smoking to produce earlier age of onset of lung cancer. We hypothesize that there are specific genotypes that greatly increase the risk of developing lung cancer, through interaction with cigarette smoking and/or other environmental agents. Our specific aims are 1. To utilize established lung cancer family research resources to identify familial lung cancer (FLC) pedigrees for genetic linkage analysis. Six established centers will accrue blood samples, tumor tissue, and risk factor data from available relevant family members in 85 pedigrees (containing 4 or more affected cases and an expected lod score (ELOD) of 0.3 or higher). Sampling has been completed for 7 extended pedigrees, and genotyping has begun on these families. We will also accrue a minimum of 125 affected sib/relative pairs, in addition to those in the 85 FLC kindreds; 2. To genotype informative individuals in the FLC pedigrees with 400 evenly spaced markers (approximately 10 centimorgans) throughout the genome. DNA isolated from blood, archival paraffin blocks will be used for genotyping both living and deceased affected and unaffected family members. We have shown that archival DNA can be genotyped with our global marker set; and 3. To map a lung cancer susceptibility gene(s) by genetic linkage analysis of the FLC pedigrees. Both parametric (lod- score) and non-parametric relative-pair methods will be utilized in the genetic linkage analyses. This research proposes to identify a subpopulation of persons who may be at a relatively high risk to develop lung cancer from even low level exposure to cigarette smoke and other environmental agents. The strategy to use linkage in high risk families has proven successful for the identification of susceptibility genes in breast, colon, and prostate cancers. While major breakthroughs have been made in understanding the genetic susceptibility basis of these other cancers, studies to identify specific major loci affecting lung cancer risk are notably lacking. The high case-fatality rate and low resection rate makes the study of lung cancer families particularly challenging because it is difficult to collect adequate numbers of biospecimens for DNA analysis. We believe only a multidisciplinary, collaborative effort to identify, accrue, and genotype FLC families will be successful in characterizing the genetic basis of FLC.